Melanoma and renal cell carcinoma represent two of the most receptive cancer histologies to immunotherapy. While a myriad of melanoma-associated antigens have been identified and vaccines based on these antigens have been evaluated in the clinic, comparatively few tumor antigens have been characterized and specific therapies have been developed for renal cell carcinoma (RCC). We have recently identified a series of peptides that derive from RCC-associated gene products that serve as target epitopes for anti-tumor CD4+ or CD8+ T cells. Of major note, our preliminary data suggest that patients with active disease, particularly those with advanced malignancy, tend to display Th2-type CD4+ T cell responses to target epitopes, while normal donors and patients that have been treated and are disease-free at the time of analysis display either mixed "Th0"-type or predominant Thl-type CD4+ T cell responses to these same epitopes. In all of these patients, Thl-type dominated responses are observed against epitopes derived from EBV or influenza viruses. In the current proposal we will extend these preliminary studies of HLA-DR4+ patients to discern the correlation of tumor antigen-specific Thl/'l'h2-biased CD4+ T cell responses with disease stage, the durability of these responses in the disease-free state and the correlation of deviation in the Thl-/Th2-type balance of tumor-specific CD4+ T cells with disease recurrence. Since the polarization of specific CD4+ T cell responses may also modulate the quality of anti-tumor CTL responses in situ, we will also evaluate whether patients with active disease exhibit Tc2-type dominated CD8+ T cell responses to RCC-associated epitopes and if Tcl-type reactivity is associated with better prognosis and disease free status. Lastly, we will analyze whether and to what extent, dendritic cell (DC)-based vaccines can "repolarize" Th2 (and Tc2)-type anti-tumor T cell immunity towards a Thl(Tcl)-type response pattern that may be most preferred in promoting clinical responsiveness, regression of disease, and maintenance of durable disease-free status.